David A. Blake

Differences in the Biotransformation of Halothane in Man

Biotransformation of 14C-labeled halothane was studied in anesthetists and pharmacists. Halothane was administered intravenously and non-lyophilizable radioactivity assayed in urine and other excreta by liquid scintillation counting. Exhaled halothane was trapped in toluene and assayed similarly. Urine was collected every two hours for 12 hours, followed by total collection for the first 24 hours and total collection for as long as 13 days. Breath samples were assayed in some cases for as long as six days after tracer injection. In two subjects the effects of concomitant halothane anesthesia were investigated. Urinary excretion of radioactivity increased when the tracer was injected into unanesthetized subjects, as compared with anethetized subject. Four of five anesthetists excreted more radioactivity than the pharmacists during the first two hours after tracer injection. This difference decreased with time. Pharmacists showed smaller variation and generally had smaller amounts of urinary radioactivity. Excretion of radioactivity may take weeks. Radioactivity was found in feces and sweat. Exhalation of halothane lasting as long as six days was found.

Animal toxicity of 2,2,2-trifluoroethanol☆

Abstract The toxicity of trifluoroethanol (TFE) was investigated in mice and dogs. In mice, the acute LD50 was approximately 350 mg/kg by the oral or intraperitoneal routes and 1.6 ml/100 ml after a 10-min inhalation. Various compounds which are known to reduce the lethality of other alcohols by blocking their oxidation to toxic metabolites were tested for their effect on TFE lethality in mice. Disulfiram, allopurinol, and 3-amino-1,2,4-triazole pretreatment were each found to provide a significant protection as the LD50 of TFE nearly doubled in each case. Sodium acetate was ineffective. Ethanol treatment for 48 hours after TFE injection markedly reduced the toxicity of TFE. Ethanol also inhibited conversion of TFE to trifluoroacetate in vivo . TFE was not oxidized by alcohol dehydrogenase and NAD in vitro ; however, TFE was a competitive inhibitor of ethanol oxidation. Mice were not killed by doses up to 800 mg/kg of trifluoroacetaldehyde hydrate or up to 5000 mg/kg of sodium trifluoroacetate. Free trifluoroacetic acid was as toxic as hydrochloric acid. No deaths occurred after 100 mg/kg of TFE ip daily for 18 days; however, the mice failed to gain weight during the treatment period. Two dogs died 48 hours after 400 mg/kg of TFE iv without significant changes in blood urea nitrogen, serum glucose, serum lactate, or bromosulfalein retention time.

Anesthesia. LXXIV. Biotransformation of fluroxene. I. Metabolism in mice and dogs in vivo.

Abstract Fluroxene has been found to undergo biotransformation in the mouse and dog after i.p. administration of subanesthetic doses. Trifluoroethanol glucuronide, trifluoroacetic acid, and 14CO2 (from vinyl carbons only) have been identified as metabolites. The extent of metabolism was increased in mice by pretreatment with phenobarbital sodium, 3-methylcholanthrene, and 3,4-benzpyrene, and these effects could be blocked by preadministration of actinomycin D. Phenobarbital pretreatment also enhanced the metabolism of fluroxene in the dog. Carbon tetrachloride-induced hepatotoxicity greatly reduced the metabolism of fluroxene in the mouse. SKF 525-A and Lilly 18947 had no inhibitory effect in mice but rather caused a slight enhancement of the metabolic activity. Repeated pretreatments with ethyl ether and nitrous oxide had a slight stimulatory action on the biotransformation of fluroxene in mice, whereas fluroxene and methoxyflurane pretreatments had no significant effect.

Inhalation studies on the biotransformation and elimination of [14C] trichlorofluoromethane and [14C] dichlorodifluoromethane in beagles.

The possible biotransformation of trichlorofluoromethane (FC-11) and dichlorodifluoromethane (FC-12) was investigated in 4 male and 2 female adult Beagles after a short (6- to 20-min) inhalation. Dogs were anesthetized with ketamine and succinylcholine, intubated, and ventilated artificially. Trichlorofluoromethane (1000–5000 ppm, vv) or dichlorodifluoromethane 38000–12,000 ppm, vv) containing up to 180μ Ci of [14C]fluorocarbon was delivered from 110-liter Teflon bags, and all exhalations were collected via a nonrebreathing valve in similar bags for 1 hr. Venous blood samples were withdrawn at appropriate times and assayed for fluorocarbon-associated radioactivity. Exhalation bags were assayed for [14C]fluorocarbon and 14CO2. Urine was collected for up to 3 days and assayed for 14C metabolites as nonvolatile radioactivity. In some experiments animals were sacrificed 24 hr after exposure and tissues were removed for determination of nonvolatile radioactivity. Essentially all of the administered (inhaled) fluorocarbon was recovered in the exhaled air within 1 hr. Only traces of radioactivity were found in urine or exhaled carbon dioxide. All tissues contained measurable concentrations of nonvolatile radioactivity 24 hr after exposure but together represented less than 1% of the administered dose. It is not possible to determine if these trace levels are associated with metabolites of the fluorocarbons or with the unavoidable radiolabeled impurities present in the administered gas mixture. Neither phenobarbital pretreatment (60 mg/day for 3 days) nor prolonged exposure (50–90 min) produced any alteration of these results. Thus, it can be concluded that FC-11 and FC-12 are relatively refractory to biotransformation after a short inhalation exposure and that they are rapidly exhaled in their unaltered chemical form.

Pharmacokinetics of Fluorocarbon 11 and 12 in Dogs and Humans

Blood levels and exhalation bag contents of FC-11 and FC-12 from dogs and humans were used to elucidate the pharmacokinetic model describing the time-course of these agents. The derived pharmacokinetic parameters were in good agreement with the physicochemical properties of these substances. The model was used to estimate the percentage of dose absorbed, which averaged 77 per cent for FC-11 and 55 per cent for FC-12, and to predict the level of FC-11 and FC-12 under a variety of conditions simulating both short- and long-term exposure to the maximum allowable concentrations of these agents. With similar doses, an 8-hour continuous exposure was estimated to produce levels of FC-11 and FC-12 that are much lower than the corresponding levels reported to induce cardiac sensitization in dogs.

Biotransformation and Elimination of 14C-Trichlorofluoromethane (FC-11) and 14C-Dichlorodifluoromethane (FC-12) in Man

Radiocarbon-labeled trichlorofluoromethane (FC-11; 14CC13F) and dichlorodifluormethane (FC-12; 14CC12F2) were separately inhaled by a female subject and a male subject. A predetermined volume of fluorocarbon (1000 ppm; 100 muCi) in air was delivered through a nonrebreating system and a tight-fitting face mask for 7-17 minutes. Total expired gases were collected during fluorocarbon exposure and afterward until no radioactivity was detectable. Expired 14CO2 and 14C-fluorocarbon were assayed. Urine was collected for 72 hours and assayed for nonvolatile radioactivity. Total recoveries of FC-11 were 99.5 and 79.4 per cent in the woman and the man, respectively. Total recoveries of FC-12 were 95.4 and 103.2 per cent. Traces of radioactivity were found in urine (FC-11, 0.07 and 0.09 per cent; FC-12, 0.02 and 0.03 per cent) and in exhaled carbon dioxide (FC-11, 0.13 and 0.10 per cent; FC-12, 0.08 per cent in both subjects). Total metabolites were equal to or less than 0.2 per cent of the administered dose. The amount of radioactivity in urine was insufficient to permit identification of possible fluorocarbon metabolites. The trace of metabolites could be products of radiolabeled impurities. (Key words: Gases, non-anesthetic, dichlorodifluoromethane (Freon 12); Gases, non-anesthetic, trichlorofluoromethane (Freon 11); Pharmacology, fluorocarbons.)

Qualitative analysis of halothane metabolites in man.

Twenty three healthy volunteers received 14C-labeled halothane intravenously. The radioactivity in their urine was characterized by the following techniques: liquid–liquid extraction, thin-layer chromatography, paper chromatography, column chromatography, inverse isotope dilution, lyophilization, and hydrolysis. The only radioactive metabolite that could be detected was trifluoroacetic acid, which appears in urine in a nonvolatile salt form.

Trifluoroethanol and Halothane Biotransformation in Man

Trifluoroethanol has been postulated to be an intermediate in the formation of trifluoroacetate during the biotransformation of halothane. As much as 80 per cent of injected C-labeled trifluoroethanol could be recovered as trifluoroacetate in the urine of two volunteers. Excretion of radioactivity lasted seven to nine days after administration of trifluoroethanol. It is unlikely that trifluoroethanol is an endproduct of halothane metabolism in man.

A note on the effect of trifluoroacetate on the growth of rat liver

SummaryThe influence of trifluoroacetic acid (TFAA) and sodium trifluoroacetate (TFA) on the liver weight to body weight ratio was measured in rats by two methods. When TFA or TFAA were added to the drinking water at a concentrate of 1 Normal, rats became dehydrated and a slight increase in the ratio was noted after ten days. However, when these substances were administered to rats (1 ml per day) by gastric intubation no change in the ratio was noted after eight days.